Abstract: For this program project we bring together a successful team of leading basic and clinical science experts to pursue research aimed at identifying novel therapeutics to address the recent surge in rates of alcohol use disorders (AUD) in women. Over the past 10 years, rates of AUD in women have increased by 84%, translating to 10.5 million women across the United States. Alcohol use is the third leading cause of preventable morbidity and mortality in the United States and women drinkers experience exacerbated health risks associated with alcohol consumption when compared to men. FDA-approved medications for AUD have low to moderate efficacy and none target factors that maintain drinking in women. A considerable body of data identifies that women are more likely to drink to regulate negative affect and stress, while men are more likely to drink for alcohol-related positive reinforcement. Across our three Projects, we will probe the noradrenergic system?s effects on stress reactivity and alcohol reinforcement. Our primary aim is to evaluate the role of the noradrenergic system to target sex-dependent factors known to maintain alcohol use in women versus men and to evaluate guanfacine as a prototypical medication to preferentially target these sex-dependent factors to improve AUD treatment outcomes.